U.S. Pat. No. 5,185,351 disclosed a variety of imidazolylalkenoic acid derivatives, processes for their preparation, pharmaceutical compositions in which they are present and uses thereof. These compounds are angiotensin II receptor antagonists and are useful in regulating hypertension induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure, and glaucoma. Among them, eprosartan mesylate, chemically (αE)-α-[[2-n-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropanoic acid monomethanesulfonate is a promising angiotensin II receptor antagonist useful in the treatment of hypertension, congestive heart failure and renal failure. Eprosartan is represented by the following structure:

As per the process described and exemplified in the U.S. Pat. No. 5,185,351 (herein after referred to as the '351 patent), eprosartan free base (obtained as per the processes described in example I of the '351 patent) is suspended in isopropyl alcohol under stirring at about 8° C., methanesulfonic acid is added rapidly to the stirred suspension, the mass cooled to 3° C. and the precipitated solid collected to give crude eprosartan mesylate. The crude eprosartan mesylate is further purified by dissolving crude eprosartan mesylate in acetic acid at 80° C., filtered through a hyflow bed at 80° C., the solution cooled slowly to 25° C. followed by stirring and then the precipitated solid is collected by adding ethyl acetate as an anti-solvent to give eprosartan mesylate.
PCT Patent Publication No. WO 97/36874 described processes for the preparation of eprosartan mesylate dihydrate. According to this publication, eprosartan mesylate dihydrate can be prepared either by i) recrystallizing the anhydrous form of eprosartan mesylate (obtained as per the process described in the '351 patent) from an aqueous solution containing an acid; or ii) mixing the anhydrous form of eprosartan mesylate with one or more pharmaceutically acceptable excipients, granulating the mixture with water, and drying the granulation to a predetermined water content.
According to U.S. Pat. No. 6,262,102 B1, monohydrated form of eprosartan mesylate is produced during the vacuum drying of the dihydrated form of this compound or when the anhydrate of eprosartan mesylate is granulated with water, stored at 50° C. overnight and vacuum dried overnight at ambient temperature.
PCT Patent Application No. PCT/IN06/000507 described an improved process for the preparation of eprosartan and its pharmaceutically acceptable acid addition salts thereof in high purity which comprises: a) reacting methyl 4-[[2-butyl-5-formyl-1H-imidazol-1-yl]methyl]benzoate with ethyl 2-carboxy-3-(2-thienyl)propionate in the presence of a base in a solvent selected from cyclohexane and n-hexane to afford a diester intermediate, namely ethyl (αE)-α-[[2-n-butyl-1-[[4-(methoxycarbonyl)phenyl]methyl]-1H-imidazol-5-yl]methylene-2-thiophene propionate, substantially free of a decarboxylate impurity namely, ethyl 3-(2-thienyl)propionate; and b) hydrolyzing the diester intermediate with a base such as sodium or potassium hydroxide to obtain pure eprosartan.
The processes described in the prior art produce eprosartan mesylate particles having the specific surface area at below 0.6 m2/g as measured by Brunauer-Emmett-Teller method (B.E.T), and the mean particle size (D50) of about 65 μm to about 75 μm and 90 volume-% of the particles (D90) of about 200 μm to about 215 μm, resulting in similarly poor dissolution and solubility properties.
Specific surface area of an active pharmaceutical ingredient may be affected by various factors. There is a general connection between Specific Surface Area and Particle Size Distribution; the smaller the Particle Size Distribution, the higher the Specific Surface Area. The rate of dissolution of a poorly-soluble drug is a rate-limiting factor in its absorption by the body. A reduction in the particle size can increase the dissolution rate of such compounds through an increase in the surface area of the solid phase that is in contact with the liquid medium, thereby resulting in an enhanced bioavailability of the compositions containing such compounds. It is generally not possible to predict the exact particle size and distribution required for any particular drug substance to achieve a specific dissolution profile or a specific in vivo behavior, as different drugs show differing dissolution characteristics with a reduction in the particle size.
Eprosartan mesylate is a white to off-white crystalline substance, soluble in methanol, but practically insoluble in water. The lack of solubility of eprosartan mesylate creates a problem since bioavailability of a water insoluble active ingredient is usually poor. Thus there is a need in the art to prepare active pharmaceutical ingredients such as eprosartan mesylate particles with a desired surface area to obtain formulations with greater bioavailability, and to compensate for any loss of surface area before formulation.
PCT Patent Publication No. WO 00/53282 disclosed eprosartan mesylate crystalline particles with a d90 value of less than 10 micron, a process for the preparation of said particles which comprises contacting a stream of eprosartan mesylate dissolved in a solvent, preferably acetic acid, with a stream of anti-solvent, preferably tert-butyl methyl ether, or colder solvent, or a solution of an appropriate acid or base, and separating off the crystals formed.
It is well recognized that preparation of tablets with a reproducible composition requires that all the dry ingredients have good flow properties. In cases where the active ingredient has good flow properties, tablets can be prepared by direct compression of the ingredients. However, in many cases the particle size of the active substance is very small, the active substance is cohesive or has poor flow properties.
The eprosartan mesylate product prepared by methods as outlined in the PCT Patent Publication No. WO 00/53282 has a very small particle size i.e., crystalline particles with a d90 value less than 10 micron resulting in similarly poor flow properties.
Thus, there is a need in the art for eprosartan mesylate with a desirable particle size distribution, which has good flow properties, and better dissolution and solubility properties.
Extensive laboratory and full-scale research has resulted in a new and inventive crystallization process producing eprosartan mesylate crystalline particles having a specific surface area of from about 0.65 m2/g to about 3 m2/g. Said particles are useful for the manufacture of directly compressed tablets. Accurate dosing in capsules may also be achieved with such particles.
Even though the U.S. Pat. No. 5,185,351 mentioned pharmaceutically acceptable salts of eprosartan, the acetate salt of eprosartan is not isolated as a solid and characterized. It has been found that the acetate salt of eprosartan can be isolated in a pure form from the crude eprosartan free base. It has also been found that the solid form of eprosartan acetate is a useful intermediate in the preparation of eprosartan free base or a pharmaceutically acceptable salt thereof in high purity.
According to one object, the present invention provides eprosartan mesylate and formulations containing eprosartan mesylate particles having a specific surface area of from about 0.65 m2/g to about 3 m2/g.
According to another object, the present invention provides eprosartan mesylate and formulations containing eprosartan mesylate particles having mean particle size (D50) ranges from about 7 μm to 60 μm and 90 volume-% of the particles (D90) ranges from about 21 μm to 150 μm.
Another object of the present invention is to provide a crystalline solid of eprosartan acetate, process for preparing it and a pharmaceutical composition comprising it.
Another object of the present invention is to provide substantially pure eprosartan free base and process for its preparation.